Portable gas operating inhaler

ABSTRACT

The invention relates to an inhaler comprising a compressed gas, such as Heliox gas in a first chamber which is in communication with an equalization chamber having pressure lower than the pressure of the gas in the first compressed chamber and having a drug storage chamber which is detachably coupled to the equalization chamber operable such that a portion of the compressed gas from the equalization chamber fluidizes and aerosolizes the drug to produce a drug cloud and which can then be injected into a spacer where it can be inhaled by a user.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of prior U.S. application Ser. No.10/845,411, filed May 14, 2004 which is a continuation-in-part of priorU.S. application Ser. No. 10/726,627 filed Dec. 4, 2003, now abandoned.

FIELD OF THE INVENTION

This invention relates to the field of inhalers used to administer adrug to a patient through the patient's lungs and, more particularly, toan improved gas inhaler.

BACKGROUND OF THE INVENTION Definitions

As used herein, “Heliox” is defined as a gas mixture of helium andoxygen whose physical properties are summarized in Table 1 depending onthe concentration of Helium.

TABLE 1 Physical properties of Heliox at 273 K, 1 atmosphere. Percentageof Helium 0 20 40 60 80 100 Density (g/L) 1.429 1.179 0.929 0.679 0.4290.179 Viscosity (μP) 204 201.2 198.4 195.6 192.8 190 Kinematic 14.3 17.121.4 28.8 44.9 106.1 Viscosity (μm² · s⁻¹)

As used herein, “ambient air” is defined as that air which normallyexists around us which is either inhaled and exhaled from theenvironment, or, pumped into a mechanical hand held device from theenvironment and then inhaled.

As used herein, “aerosolization” is primarily defined as the generationand then breakup of a liquid sheet into primary and satellite droplets,generally 1 micron to 20 microns in size, although the physical form ofparticles in an aerosol as used herein may be liquid drops or solid drypowder particles.

As used herein, “fluidization” is defined as the deagglomeration of acompact mass of drug in micronized dry powder form manufactured with apreferred particle size range of 1 micron to 5 microns into a cloud,with the objective being the generation of particles in the preferred1-10 micron range, and more preferably in the 1-3 micron range.

As used herein, “heterodisperse aerosol” or “heterodisperse particlecloud” shall be defined as a deliverable form of a liquid drugformulation or dry powder drug formulation, such that there areparticles of many different sizes.

As used herein, “monodisperse aerosol” or “monodisperse particle cloud”shall be defined as a deliverable form of a liquid drug formulation ordry powder drug formulation, such that the particles are all the same,or very near the same size.

As used herein, “alveoli” are air sacs deep in the lung at the terminalend of the smallest and last branch of bronchioles, where gas exchangetakes place between the airspace in the lungs and arterial blood. Smallparticulate drug matter can enter the alveolar spaces, depending ontheir size and deposition characteristics. After entering the alveoli,the drug matter becomes engulfed by alveolar macrophages, which existaround each alveolus under its surfactant layer and enter the acinus byway of the terminal bronchiolar lumen. Drug particles may be absorbedfrom the lung primarily by alveolar macrophages.

As used herein, “fine particle dose” shall mean particles that arepreferably about 5 μm or less, generally 3 μm or less, and morepreferably 2 μm or less.

As used herein, “respirable fraction” (RF) is a dose fraction ofaerosolized drug particles small enough in diameter to escape thefiltration machinery of the airways and be deposited in the lungs.

As used herein, the terms “dry powder formulation” and “liquidformulation” are pharmacologically active drug by itself, or with any ofthe following including but not limited to propellants, carriers,excipients, surfactants, anti-microbial, flavoring, and other additionsto the formulation that enhance production, shelf life stability,generation of particles, delivery to the desired site in the lungs, andabsorption, macrophage or other processed base transfer from the airspace into the tissue and blood, or taste.

General Medical Background

Delivery of therapeutic drugs via the lungs for respiratory andnon-respiratory systemic diseases, is increasingly being recognized as aviable if not superior alternative to administration of drugsorally/nasally, rectally, transdermally, by intravenous needleinjection, intra-muscular needle injection, or gas jet driven non-needleinjection through the skin and into the muscle.

Around 1 million patients in the US receive intravenous morphine for therelief of chronic and terminal pain. Morphine actually acts more rapidlywith respect to pain management when inhaled than when injected. Inaddition, there is a major effort to move away from CFC or other vaporpressure based propellant driven inhalers toward alternative technology,due to environmental issues.

All but oral and rectal modes of administration, ideally require aliquid form of drug. Hard particulate drug forms are being explored forgas jet driven needle-less injection through the skin for deposit intothe muscle for extended or timed release of the drug substance.

In each of these non-pulmonary methods of drug administration, farhigher doses of drug substance than that required for actual therapeuticeffectiveness on the target system must be administered to assure thatthe required therapeutic amount of drug substance is actually deliveredto the target system or site. This represents a risk factor to thepatient, in that there is a therapeutic variable regarding the amount ofdose delivered to the target system or site. The exception is where thattarget is very local to the site of administration (i.e., mouth, colon,patch of skin, area of muscle, etc).

In addition, many new drugs being developed by companies in thebiotechnology field based on peptides and proteins, exist as dry powderin their optimum and/or most stable form, and so these drugs cannot beinjected using a needle or needle-less method, or administeredtransdermally. Genetically produced peptide and protein based drugs arealso very sensitive to being altered by in-vivo environmental factorssuch as enzymes and acids.

If such sensitive drug molecules in dry powder form are deliveredorally, they are subjected to the enzymes and acids in the digestivetract. This can reduce the quantity of these sensitive therapeuticmolecules available for absorption into the blood in their originaltherapeutic structure, increasing the need to initially deliver a higheroral dose. Rectal drug administration is neither pleasant, sociallyacceptable, or commercially viable except in extreme cases where noother choice exists.

The intravenous needle method of administering therapeutic drugs inliquid form in the arm or femorally, results in the dilution and loss ofadministered drug potency as the blood passes through the venous systemback to the heart, then to the lungs, and finally into the arterialcirculation for delivery.

Intra-muscular needle injection adds a pathway where part of theadministered dose can be lost. The same is true for a gas driven jetneedle-less injection, where the drug substance must go through theskin, into the muscle, (usually and primarily) into the venous bloodsystem, and then into the arterial system.

Hence, it is necessary to inject more drugs, regardless of the method,than is really needed to achieve the desired therapeutic effect on, forexample, a specific organ system or organ based receptor target fed byarterial blood. However, by introducing a drug substance into thearterial blood stream at its source, the lungs, a bolus of drugdelivered to the target is less diluted, and, therefore, less drug needsto be deposited in-vivo at the site or entry point of administration(the alveoli).

Delivery of drugs via the lungs is the optimal approach to treatdiseases in the lung. In addition, drugs delivered via the lungs forother than respiratory diseases, go rapidly and directly into thearterial blood, then to the heart, and then to the other critical organssuch as brain, liver and kidneys, and receptor sites residing thereon.This reduces the effect of dilution on the administered therapeutic dosein the bloodstream. Furthermore, there is minimal enzymatic or acidactivity in the lungs compared to the stomach that can impact thetherapeutic molecular integrity of sensitive drug molecules such asgenetically engineered peptides and proteins. Pulmonary drug deliverycan, depending on the drug and disease:

-   -   a) improve the efficacy of a drug;    -   b) improve the bioavailability of a drug, which is particularly        important for biological compounds such as peptides and        proteins;    -   c) improve targeting to an organ or receptor site thus reducing        unwanted side effects (which is an important consideration with,        for example, anticancer agents); and    -   d) mimic the biopattern of a disease, or circadian rhythm, e.g.,        as in the case of sustained-release anti-hypertensives designed        to peak coinciding with the early morning blood pressure surge.

Commercially, a new method of pulmonary drug delivery for an existingdrug, can extend its therapeutic indications, lower cost, and facilitatea more rapid time to market. Since drugs administered by the pulmonaryroute do not require sterility, a sterile device or sterile environment,they are ideal for the delivery of drugs in difficult environments.

U.S. Pat. No. 6,125,844 discloses an apparatus for portable gas-assisteddispensing of medication not using a fluorocarbon propellant. Theapparatus comprises a pressurized supply of gas containing therapeuticgas or mixture of therapeutic gases, and one or more drugs mixedtherein, connected to a pressure regulator, wherein the pressureregulator is connected to a gas release switch which is connected to abreath activator. The breath activator is connected to an aspirationchamber, whereby in use when a patient inhales from the aspirationchamber, the inhalation causes the breath activator to engage with thegas release switch to release the therapeutic gas/drug mixture into theaspiration chamber, wherein the therapeutic gas and drug in theaspiration chamber are simultaneously delivered to a patient duringinhalation. Alternatively, medication can be stored in a separate drugreservoir adjacent the pressurized supply of therapeutic gas, whichmedication is drawn into the aspiration chamber by a venturi assembly.

Variables that affect inhaler generated particulate drugs beingdelivered to the right location routinely mentioned in the medicalliterature include:

a) those that are breathing related including the volume of inspiration,inspiration flow rate (velocity), breath holding period afterinspiration of a dose, the total lung volume at the time the bolus ofmedication is administered, and the expiration flow rate;

b) those that are particulate related including aerosol particle size,shape, density of the liquid or powder drug particles, and sizedistribution in the dry powder or liquid aerosol cloud produced; and

c) the medical status of the patient, and in particular, the status ofthe respiratory system of the patient.

The objective with any method and technology involving inhalers, is: a)to generate particles of the optimum size range for deep lung delivery,and b) to get any administered particles past the larger airways wherethey will be lost to turbulence and impaction and into the middle (fortreating respiratory diseases) and deep (for delivering drugs to thetarget area where they can enter the arterial blood) lung.

Unlike intravenously administered drugs, drugs administered via thelungs are not subject to prior first pass hepatic metabolism. They arealso less subject to reacting with or being affected by fewer receptorsprior to reaching their intended target either in the lungs orsystemically, resulting in a reduced amount of drug being needed, if theparticle size and delivery to the target location in the lungs areoptimized. However, because any systemic drug administered by the lungdoes go straight to the heart first, the cardiac side effects ofexcipients and drugs administered by this method are an issue. As anexample of the rapid effects drugs administered via the lungs can havesystemically, administration of the pain killer morphine via the lungsis faster acting than morphine administered intravenously.

Recognition of the ability to deliver systemic therapeutic drugs byinhalation due to the physiological properties of the lung andcirculatory system, has led to a large number of different therapeuticdrugs being developed and evaluated for administration by inhalation totreat even non-respiratory diseases.

A key problem is in the maximizing the number of these smallestparticles that are delivered to the terminal branches of the bronchiolesand the alveoli. Small particles, preferably 1 μm-3 μm in size, areoptimal for this purpose. Generally, only about 10-20% of the amount ofparticulate drug dispensed by conventional inhalers is delivered in thisrange.

Large molecule drugs, such as peptides and proteins which are nowpossible due to genetic engineering, do not pass easily through theairway surface because it is lined with a ciliated mucus-covered celllayer of some depth, making it highly impermeable. The alveoli however,have a thin single cellular layer enabling absorption into thebloodstream. The alveoli are the door to the arterial blood and are atthe base of the lungs.

So, to reach the alveoli, a particulate drug must be administered insmall size particles, and the inhalation must be moderated, slow, anddeep. Large particles will impact in the oropharyngeal area or settle inthe upper bronchi. If the particles are too small and/or ultra light,they will be exhaled (the latter is especially true if air is the tidalfront of gas entraining the ultra light particles).

The larger passages through which the air and drug particles travelgenerates turbulence, which also results in the impaction and loss ofdrug particles. A desired goal is to increase the laminar flow of thegas stream in the larger air passages, so that particles reach thesmaller passages where laminar flow is naturally induced. If there areany constrictions in the bronchi or bronchioles, resulting, for example,from asthma, the turbulence and rate of impaction of drug particles canalso increase at those points of constriction.

Any variability in the dose deposited in the lungs, and where it isdeposited in the lungs, could have a major effect on treatment becauseof the narrow therapeutic range of many drugs, and the potency of suchdrugs. One well known such example is insulin.

Aerosol particles are deposited in the airways by gravitationalsedimentation, inertial impaction, and diffusion. All three mechanismsact simultaneously. However, the first two are the principle methodsthat apply to the deposition of large particles. Diffusion, is theprimary factor of deposition of smaller particles in peripheral regionsof the lung.

The optimum size particles of drug for delivery to the alveoli are inthe range generally of 1-3 microns, and usually particles less than 2microns reach the alveoli.

The diameter of therapeutically usable particles is generally between0.5 and 5 microns. Particles 1-5 microns are deposited in the largerairways while particles generally below 3 microns in diameter reach theterminal bronchioles and alveoli and are optimal for transference intothe arterial blood. The depth of penetration of a particle into thebronchial tree is inversely proportional to the size of the particle,down to 1 μm. Particles smaller than 1 μm, however, are so light that alarge proportion does not deposit in the lungs.

The small airways are the optimal sites for the inhalative treatment ofobstructive pulmonary diseases. Diffusion is a process that applies toparticles smaller than about 3 microns. The maximum collection ofparticles by the deep lung is by the process of sedimentation.

Some of the sub-micron particles of a drug may be exhaled because theirsedimentation may not be high enough in air—which is normally theambient entrainment gas and environment in the lungs.

Prior art, whether metered dose inhalers (MDI) or dry powder inhalers(DPI), use air as the exclusive or primary means of conveying fluidizedpowder or aerosolized liquid drug into the lungs. In the case of MDIs,it is assumed that the propellant evaporates as intended or constitutesa very small fraction of the total gas inhaled at full tidal volume withthe drug dose and air.

Heliox has been administered to a patient in a hospital setting prior tothe administration of a dry powder or liquid aerosol drug. Heliox hasalso been used to administer a liquid drug using a nebulizer, which is adifferent type of device for pulmonary drug administration lasting 10-60minutes. That is distinct from “puffs” received through an inhaler.Additionally, in both cases, the systems in which Heliox were used weredesigned for the physical properties of air and not Heliox, and so werenot optimized for Heliox.

Prior art and medical publications pertaining to inhalers, address otherfactors but do not focus on the specific gas involved in the transportof particles into the lung. In the case of DPIs, the gas is alwaysassumed to be, or stated specifically to be, air. In the case of MDIs,the “gas” is always assumed to be a liquid propellant having a vaporpressure, CFC in most cases, and is only a negligible fraction of theinhaled volume, the balance being air.

MDI is a metered dose inhaler consisting of a propellant generating avapor pressure and a drug in suspension or solution form, where, whenthe device is activated, the vapor pressure of said propellant pushes apredetermined amount of liquid drug through a nozzle generating anaerosol for inhalation. MDIs contain suspensions or solutions of a drug,a propellant, and a surfactant that acts as a lubricant to stopparticles from aggregating and to reduce clogging of the aerosol nozzle.MDIs rely on the use of propellants that have a high vapor pressure. Thehigher the vapor pressure, the faster a liquid containing a drug can bepushed out of a nozzle, and thus a thinner liquid sheet is formed, andsmaller particles are produced. Vapor pressure is therefore directlyrelated to the velocity generated and the fraction of fine or desirablesmall particles generated.

Pressurized aerosols historically used chlorofluorocarbon (or CFC)propellants generating a pressure of approximately 400 kPa or higher.The aerosol cloud therefore emerges from the canister at a high speed.Furthermore, the drug crystals are initially enclosed within largepropellant droplets whose mass median diameter may exceed 30 μm. Largeparticles traveling at high velocities are very susceptible tooropharyngeal deposition by inertial impaction. While the propellantevaporates and the particles slow down when the device is held away fromthe mouth, or when an MDI spacer is used, on average, only about 20% ofthe original or nominal dose actually enters the lungs.

In an MDI, the generation of an aerosol occurs in what can only bedescribed as an explosive manner since the propellant containing thetherapeutic solution or suspension disintegrates as it passes throughthe aerosol nozzle at very high velocity. As the propellant flashrapidly evaporates, the liquid particles decrease rapidly in diameter tothe state of a “dried solute”.

The velocity of the discharged particles entrains the evaporatingparticles as they exit the device and move into the airstream. Thisvelocity is much higher than an inhalation velocity by a user. Theresult can be impaction of particles in the oropharyngeal area. Aspacer, which is discussed later, is a solution to this problem, i.e.,reducing the velocity of the “cloud” of particles prior to inhalation.Another technique is to use the “open-mouth” method that impliesactivating the device a few cms away from an open mouth.

MDIs containing a suspension require that they be shaken before use.MDIs containing a solution need not be. This presents a problem topatients using more than one type of drug, i.e., one in suspension andone in solution, as the patient may shake the wrong MDI, or not shakethe MDI that needs to be shaken before use. The latter one would resultin an incorrect dose of the drug being delivered and inhaled. This is anadvantage to the use of DPIs, as there is no “to shake or not to shake”decision. MDIs containing propellant and a suspension or solution, alsopresent a challenge concerning stability over a temperature range.

A problem with both MDIs and DPIs is that there is often poorcoordination between the patient pressing the actuator and the timing ofthe inhalation. One solution is to use a spacer between the device andpatient, that will also allow for the heavier particles to settle beforethe patient inhales.

Another problem with MDIs is that they are based on propellants thatrely on vaporization to generate pressure, and a drop in temperatureoccurs when vaporization occurs. The vaporized propellant can hit theback of a user's throat before it has completely evaporated if no spaceris used. This can lead to reflex gagging which interrupts the continuousand deep inhalation required for optimum delivery of the drug. Inaddition, water moisture in the mouth will con dense rapidly in the coldvapor, causing the small liquid medication droplets to coagulate anddrop out, reducing the percentage of drug actually deliverable past theoropharyngeal area.

DPI is a dry powder inhaler consisting of a drug in micronized drypowder form provided in a compact shape and contained in a unit dosecontainer or reservoir, which is fluidized by the flow of a gas andinhaled by the patient.

Micronized dry powder formulations are very soluble and quickly dissolvein the fluid layer on the surface of the deep lung before passingthrough the thin single cellular layer of the alveoli. They are thendeposited in the alveolar region and can be absorbed into thebloodstream without using what are commonly referred to as penetrationenhancers. Dry powder aerosols can carry approximately five times moredrug in a single breath than metered dose inhaler (MDI) systems and manymore times than liquid or nebulizer systems.

Micronized dry powder drugs used in inhalers are usually produced withan original particle range of 1-10 microns. An individual dose as loadedcan take from 5 mg to 20 mg of dry powder drug. A lower total amount ofdry powdered drug is possible with purer drugs, or with drugs that donot require or are packageable without excipients. Examples of excipientcarriers used in dry powder drug formulations include lactose,trehalose, or crystalline or non-crystalline mannitol. Trehalose andmannitol, which are spray dried sugars, are better dispersal agents thanlactose.

Thus, the “drug substance” in a DPI consists of the pure drug, plus asugar if an excipient is used, compared to the multitude of constituentscontained in a MDI. This multitude of constituents in a MDI increasesthe work involved in production of the product and its packaging, caneffect formulation stability, can cause aerosolization problems byclogging the nozzle, and may require either the shaking or non-shakingof the MDI Inhaler before use.

In DPI devices, providing compressed gas or propeller/impeller assistedfluidization, basing the fluidization on the patient's inhalationproduces a major variability in dosing and particle size formation. Thevelocity, ramp up rate, and continuous event of this inhalation arevariables that can effect the fluidization of the powdered drug and theeffective delivery of the optimum size particles to the deep lung. Thehigher the rate of gas velocity, the finer the particle size createdduring fluidization, but the greater the possibility for impaction ofparticles in the oropharyngeal area during inhalation, where the gasvelocity which fluidizes the dry powder drug is derived from the“suction” or negative pressure of a strong inhalation.

Devices that rely on the force of the patients inhalation, also operatebased on the “suction” or pulling effect of said gas flow, i.e. anegative pressure, to pull apart and fluidize the drug powder. This isless effective than a highly focused directed stream of high pressuregas, which is consistently delivered at the same pressure.

Some DPIs use compressed air generated by a pumping mechanism, which thepatient utilizes, whereby the pressure is released for fluidization ofthe powder drug when the system is actuated. The pressure, and thereforevelocity, of a gas that can be generated by a hand pump or an inhalerdevice, is far less than that available from a compressed gas cartridge.The uniformity of fluidization of the dry powder would therefore be lessusing a manual hand pump, with the possibility therefore of generatinglarger percentages of larger size particles, which result in thevariable and inconsistent loss of drug in the oropharyngeal and upperbronchi.

The higher the velocity of the gas hitting the dry powder, the greaterthe amount of powder dislodged and the turbulence induced, which cancreate a cloud of particles for inhalation. In the case of dry powderinhalers, the ramp speed to the velocity required to deaggregate ordeagglomerate the dry powder into fine particles, is as important afactor as velocity in determining effectiveness.

Systems using dry powder drug in capsules, require the patient to loadthe capsules individually, whether the system is capable of being loadedwith one dose at a time, or several doses for multi dose use over time.In some of these devices, the capsule is crushed to thereby release thepowder contained therein.

A DPI entrains the fluidized drug powder and sends it through a narrowgap, increasing the velocity of the gas and powder to improvedeagglomeration by turbulence and reduce the number of large particlesby impaction or settling out. Often, a baffle is also included in thesystem to trap larger particles.

One problem in using compressed gas vs. a hand pump to generatecompressed air DPI (or a liquid MDI driven by CFC vapor pressure) isthat the compressed gas pressure will decrease with usage. In the caseof the hand pump driven DPI, the gas pressure is consistent during eachdose fluidization procedure. In the case of gas driven MDIs, thepressure available for aerosolization decreases over time near the endof the capacity, unless the MDI has a cut off which does not allow doseadministration below a certain minimal pressure required to achievesufficient aerosolization.

A spacer is a plastic or metal tubelike device that is placed betweenthe inhaler device and the patient, and into which the inhaler devicedelivers the particulate cloud generated by dry powder fluidization orliquid aerosolization. A spacer can be open-ended, allowing a slowingdown of the gas, or closed-ended (holding chamber) to reduce the loss ofdose inhaled due to poor hand-breath coordination. The spacer slows downthe gas mass and particles leaving the inhaler, traps larger particlesby impaction and settling, and provides a better control of inhalationrate and timing, delivery of the desired size range of particles, andreduced oropharyngeal loss of particles due to impaction, versusinhaling directly from the inhaler device. It also reduces the gaggingeffect from inhaling a cold gas like Freon. Spacers have beenincorporated into the routine use of MDIs.

Inhalation flow velocity in inhalation driven inhaler determines thequality of the aerosol cloud, as the greater velocity fluidizing the drypowder drug, the finer the particles produced. However, the inhalationof particles at a fast rate, leads to impaction of a large percentage ofparticles on the back of the throat.

Heliox, which is commercially available in a combination of 70% or 80%helium in oxygen, has been used for over 70 years in respiratorytherapy. Heliox is administered in some hospitals and emergency rooms inlarge gas cylinders. The most popular types are the “K” cylinder thatstands 51 inches in height, 9 inches in diameter and weighs 1301 b whenfully filled. Heliox is supplied at 2,200 psig and requires a two-stagepressure regulator to reduce the pressure for administering to patients.However, due to its bulkiness and requirement of sophisticated pressureand flow regulators, it is used only in research and hospitalfacilities.

Gas flow within the tracheobronchial tree is complex and depends on manyfactors. For a given pressure gradient, the volumetric flow rate of agas is inversely proportional to the square root of its density. Inaccordance with the subject invention, it has been found thatsubstituting helium for nitrogen in inhaled gas mixtures results inincreased gas flow rates because the density of helium is much lowerthan that of nitrogen.

Resistance to the flow of gas within the tracheobronchial tree resultsfrom convective acceleration and friction. Convective acceleration isthe increase in the linear velocity of fluid molecules in a system offlow in which the cross-sectional area is decreasing. Frictionalresistance may be either turbulent or laminar depending on the nature ofthe flow. Since resistance associated with these factors isdensity-dependent, breathing a less dense gas should decrease flowresistance and, consequently, reduce respiratory work. An obstruction inthe upper airway causes a resistance to flow that is primarilyconvective and turbulent and therefore susceptible to modulation througha change in gas density. For respiratory treatment, it is desirable tocreate a flow of minimum pressure drop or flow-resistance.

Gas flow in airways may be laminar, turbulent, or a combination of thetwo. Turbulence is predicted by a high Reynolds number, which is aunitless quantity proportional to the product of gas velocity, airwaydiameter, and gas density divided by viscosity. The Reynolds number isalso expressed as the ratio of kinetic to viscous forces. The decreaseddensity of helium, when substituted for nitrogen, lowers the Reynoldsnumber and may convert turbulent flow to laminar in various parts of theairway. Turbulence is highly dependent on the surface roughness, so thata flow in a rough cavity might be turbulent even if the Reynolds numberpredicts a laminar flow. Even in the absence of turbulent flow, thedecreased density of helium improves flow and decreases work ofbreathing along broncho-constricted airways.

The efficacy of Heliox in respiratory therapy occurs because it is alow-density gas. The rate of diffusion of a gas through a narrow orificeis inversely proportional to the square root of its density (Graham'sLaw). When an area of stenosis occurs in the airway, there is resistanceto flow at the site of the stenosis. The resistance varies directly withgas density. Downstream from the stenosis, airflow becomes turbulent. Bysubstituting helium for nitrogen in inspired air, resistance at stenoticareas is reduced and turbulence downstream from the stenosis is eitherreduced or eliminated.

In the tracheobronchial tree, a laminar flow normally exists in airwaysthat are generally less than 2 mm in diameter. Turbulent flow has beenobserved in the upper respiratory tract, the glottis, and the centralairways. This upper portion of the airway, especially the throat, andthe main bronchioles, are considered to be the region where theturbulent intensity is sensitive to the gas density.

Since airway resistance in turbulent flow is directly related to thedensity of the gas, Heliox, with its lower density than nitrogen oroxygen, results in lower airway resistance. Heliox further lowers airwayresistance by reducing the Reynolds number, such that some areas ofturbulent flow are converted to laminar flow. The higher flow rate ofHeliox has the ability to stay laminar at velocities under which airwould be turbulent.

Heliox does not need to be laminar to provide higher flow rates and itsbenefits persist under turbulent conditions. Some have the misconceptionthat, due to its lower density, helium is less viscous than air, so itflows faster. Actually, the absolute viscosity of helium is slightlyhigher than that of air, and its kinematic viscosity (absolute viscositydivided by density) is about seven times that of air. Thus, from thefluid-dynamical standpoint, helium is more viscous than air.

The linear relationship between helium concentration and resistance toflow is predictable on the basis of fluid mechanics. Helium has twomajor effects in reducing resistance in an obstructed airway. First,helium reduces the probability of turbulence. Flow of air in the upperairway is turbulent, except at rest, because of the rough walls of theairway and the relatively short lengths of the airway segments comparedto their diameters.

The probability of turbulent flow is predicted by the Reynolds number:

$\begin{matrix}{{Re} = \frac{\rho \; {VD}}{\mu}} & (1)\end{matrix}$

where

-   -   D=Diameter of the mouth, airway or throat (cm)    -   V=Gas velocity (cm/sec)    -   ρ=Density of the gas (g/cc)    -   μ=Viscosity (g/cm/sec)

Second, gas flow through an orifice requires an increase in pressure tomaintain the flow:

$\begin{matrix}{U_{o} = {\frac{C_{o}}{\sqrt{1 - \beta^{4}}}\sqrt{\frac{2\left( {P_{a} - P_{b}} \right)}{\rho}}}} & (2)\end{matrix}$

where P_(a)-P_(b) is the pressure difference caused by the orifice(dynes/cm²), and C_(o), is the discharge coefficient, which depends onthe sharpness of the edge of the orifice.

-   -   U₀=Velocity through the orifice    -   β=Ratio of orifice diameter to pipe diameter    -   P_(a)=Pressure at upstream before orifice    -   P_(b)=Pressure at downstream after orifice.    -   ρ=Density

In summary, Heliox is more beneficial because of its lower density.Compared to air, it flows at a higher flow rate for fixed pressuregradient, or needs a lower pressure gradient or work of breathing (orpatient inhalation effort) for a given flow rate. This is valid even inturbulent conditions.

There is medical literature where Heliox has been provided to a patientprior to dosing with an Inhaler based on a CFC based propellant. Thereis also a study where a small volume of Heliox (40-70 ml) was deliveredas bolus but with a shallow breath during pulmonary administration of aparticulate to see if the entrained particles would diffuse deeper intothe lungs by themselves within the Heliox gas.

There is also literature where Heliox was used with a nebulizer todeliver a drug in liquid form. Most of the time, the velocity of thenebulizer gas flow was based on that used for air. In other cases wherethe gas flow velocity was altered, the aerosol nozzle used was designedfor air and not Heliox or pure helium, so that the particle sizedistribution was not adapted to the change of gas.

Two factors that can influence the delivery of an optimally fluidizeddry powder drug formulation are static electricity and humidity. It isdesirable to avoid imparting a static electricity charge to the fineparticles, especially those 1 micron or less in size. The static chargewill form an attractive force on the particles, causing them to clumptogether, rendering them of a collective size that is unsuitable fordeep lung delivery. This type of particle cohesion is highly undesirablebecause a few particles that are attracted together can double or triplethe terminal settling velocity. This is a key reason why conventionalinhalers using inhaled air, propeller driven air, or compressed airpumps, have more than 50% of the drug lost in the mouth and throat,before they can enter the lung.

Moisture in the fluidization gas can also result in the clumping ofparticles. This is a disadvantage of using inhaled air, air from thesurrounding environment driven through a propeller, or air compressedusing a hand pump that is part of an inhaler. If an inhaler is used in ahumid geographical location or during humid seasonal conditions, thehumidity can affect the deliverable dose of drug particles in the sizerange required for penetration into the deep lung, thereby affecting thedose.

In addition, if moisture comes in contact with the powder before it isfluidized, the moisture can accumulate on the outer layer of the powder,forming lumps before fluidization occurs.

The subject invention system can be light enough to be portable, andsmall enough for a child up to an adult to hold and use.

It is an object of the subject invention to provide an inhaler that candeliver appropriate sized particles to the lungs efficiently using apropellant with sufficient pressure to fluidize or aerosolize a drug tobe used by a patient.

SUMMARY OF THE INVENTION

The present invention describes in detail an inhaler for medicalpurposes where the main carrier gas is Heliox or helium. One embodimentof the invention is an inhaler for introducing a drug into a user, saidinhaler comprising:

a first chamber adapted for containing first a compressed gas at a firstpressure;

a second chamber in selective communication with said first chamber,said second chamber adapted for containing a second compressed gas at asecond pressure lower than the first pressure, said first and secondchambers cooperating so as to yield said second pressure of saidcompressed gas within said second chamber;

a means to administer two different volumes of gas in successiveapplications from the second chamber;

a storage section coupled to said second chamber, said storage sectionadapted for containing a drug and operating such that a portion of saidsecond compressed gas can fluidize and aerosolize said drug to therebyproduce a drug cloud; and

a mouthpiece coupled to said storage section, said mouthpiece adaptedfor receiving said drug cloud and convey said drug cloud to a user.

The inhaler is comprised of three mostly independent parts: ahigh-pressure canister, a drug delivery holder, and a spacer. The threeparts can be separable from each other or affixed in a non-separableway. The canister can have a resealable, refilling opening and the drugholder can be removable and have a resealable refilling means. The highpressure canister holds pressurized Heliox or helium and delivers twoconstant volumes of gas at a fixed pressure independently of the insidepressure of the canister. One volume of gas can go directly to thespacer to purge it from ambient air, while the second, smaller, volumeof gas will interact with the drug. The drug drum holds several doses ofdrug in liquid or powder form that will be nebulized or liquefied usingthe second volume of gas from the canister. Finally a spacer is used tohold and mix the two volumes of gas from the canister and opens up tothe patient. Alternatively, only one volume of gas can be released bythe canister to purge and nebulize the drug in one process.

These aspects, as well as others, will become apparent upon reading thefollowing disclosure and corresponding drawings. The drawings will coveronly some embodiments of the invention to explain its overallfunctionality. There is wide room for design changes on the technicalaspect of the gas delivery for instance. No figure is drawn to scale.

In order to position a helium/Heliox canister on the market, it isnecessary to produce a product of similar weight and dimensions ascurrent MDIs. The weight when full is estimated at 50 grams. Heliumitself is a light gas and will contribute only slightly to the overallmass of the canister. Indeed, 300 ml of pure helium weights 50 mg, so100 doses of 300 ml would only weight 5 grams.

It is hence preferable to minimize the weight of the canister. Itssizing, however, depends on the inside pressure of the gas, but pressurewill limit the total amount of gas in the device, or the total number ofdoses available. We will base our calculations on average canisterdimensions of 80 mm height by 40 mm diameter, containing roughly 100 ccof gas. Assuming 10 doses, or 3 liters of gas, the canister will need tobe pressurized at 500 psig. The device would then weight 50 grams usingsteel (stainless or carbon). If we want to deliver 50 doses (comparableto existing MDIs), the canister should then be pressurized at 3,200 psigand will weight 320 g (steel). See Table 2 for details.

TABLE 2 Design of proposed canister. Number of doses 1 10 50 Insidepressure (psig) 50 500 3,200 Volume of gas (liters) 0.34 3.3 15Thickness (mm) 0.05 0.5 3.2^(a) Weight Full (grams) 5 50 320 Height 80mm, diameter 40 mm (dimensions based on existing MDIs). ^(a)The overalldimensions of the canister are changed due to the high thickness.An optimization of the dimensions of the canister can be easily done soto have an acceptable overall weight, inside pressure and number ofdoses available. For instance a 25 cc container at 1,600 psig can alsodeliver 10 doses, while weighting 30 g.

A helium canister can not compare to existing MDIs as described herein.For a similar number of doses, it will be too heavy and pressurized atdangerous levels. This is due to the fact that the canister needs a muchhigher amount of gas per dose to fully use helium properties.

The solution is to design the canister for a very limited number ofuses. Synchronizing the number of available doses in the canister withthe number of drug packages in the drum (plus a residual volumenecessary to delivering the gas) ensures that patients will neveroperate their devices without the necessary drug. A cylinder containingthe necessary amount of helium/Heliox for 10 doses would weight roughly40 grams full (37 grams material, less than 1 gram for the gas), whichis comparable to existing devices. Finally it would market itself alongwith existing DPIs in terms of number of available doses, but with amuch better efficiency due to the use of Heliox/helium for better drugdelivery and the absence of patient hand-breathing synchronization.

In order to help leverage the cost of the inhaler over longer period ofuses, the canister can be refillable. In this case, the user would alsohave a bigger, high-pressurized helium/Heliox cylinder at home and wouldrefill his small inhaler canister with a simple process after a certainnumber, 10 for instance, of uses. This idea is novel to inhalers andwould allow the patient to use their inhalers for months at a timewithout a refill from health care providers. In this case, the drug drumcould be allowed to contain a much higher number of doses. Refilling thecartridge could be done with no or very little modification to thecurrent proposed cartridge and gas delivery designs.

The canister's maximum pressure is 500 psig. An E-cylinder is typicallyfilled up to 2,200 psig for a total content of 623 liters for 100%helium or 708 liters for pure oxygen. Using an E-cylinder to refill thecanister with a basic regulator set up for a delivery of 500 psig wouldallow refilling the canister with 1,600 doses or 480 liters based on thecontent for the helium E-cylinder.

Practically, the in-home Heliox tank would have a standard regulator setup for a delivery of 500 psig. The easiest way to refill the canister isto have a separate valve on the canister for refilling purposes only.The valve could be similar to a standard one-way refilling valve as usedon footballs for instance and located on top or on the side of thecanister to avoid any interference with the metering chamber inside thecanister. For aesthetic and safety reasons, it is preferable that noextension protrudes from the cylinder. The valve would only open if theproper stem from the in-home refilling tank is inserted and, due to theregulator of the home cylinder, would refill the portable cylinder toexactly 500 psig, or 10 doses. The operation would only require the userto push the cylinder on the valve stem and would last a few seconds. Apressure gage on the home cylinder would let the user know when theinside pressure falls below 500 psig, the pressure when the cylinderwould be considered having reached the end of its usable life.Alternatively a counter device would let the user know how many refillsare available in the home cylinder.

The whole refilling system would only require the regulator on top of astandard medical cylinder along with the specific valve stem and thepressure gage or dose counter. This clearly limits the overall cost ofthe device. Renting the home cylinder to the user would further reducethe costs by reusing the device and refilling it in specializedfacilities in a similar fashion to existing Oxygen cylinders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an inhaler, diffuser, and spacer in accordancewith the invention;

FIG. 2 side view of a piston-chamber assembly to deliver the two volumesof gas;

FIG. 3 is a an alternative to FIG. 2 to deliver the two volumes of gasusing two gas orifices, one being a calibrated orifice;

FIG. 4 is side view of a drug drum assembly;

FIG. 4A is a sectional view of A-A of the drum of FIG. 4 used to hold adrug in accordance with the invention;

FIG. 5 is an alternative to FIG. 4.

FIG. 6 is a side view showing the engagement of the drum and anequalization chamber;

FIG. 7 is an enlarged side view of a tube containing a liquid drug;

FIG. 8 is an enlarged side view of an alternative embodiment of a tubecontaining a liquid drug;

FIG. 9 is a side view of a tube adapted to be coupled to a fixed nozzle;

FIG. 10 is a side view of an alternative coupling of a tube with a fixednozzle;

FIG. 11 is a side view of a spacer in accordance with the invention;

FIG. 12 is a side view of another embodiment of an inhaler and diffuserin accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Referring to FIG. 1, there is shown an inhaler 30 in accordance with theinvention. Inhaler 30 comprises a high pressure chamber 32 coupled to anequalization chamber 34. High pressure chamber 32 is a small, coldrolled, low carbon steel container containing gas 52 compressed to apressure between about 30 psig and about 1600 psig, preferably between100 psig and about 500 psig. Gas 52 is a gas preferably containing from0% to 100% of helium, the balance if needed being oxygen. Othercompressed gases could also be used. It is preferred that the gas thatis used be a dry gas. The high pressure storage allows Heliox to bestored in a container preferably 10 cc to 100 cc in volume but stillprovide sufficient gas for a large number of inhalations. For example,100 cc of Heliox at 200 atmosphere will expend 200 times in volume to avolume of 20 liters when the gas is released to atmospheric pressure.

To provide Heliox at a constant pressure, the storage pressure inchamber 32 should be significantly higher than the regulating pressure.When the supply pressure of the compressed Heliox falls below thepressure required to fluidize the powder (or aerosolize a liquid) to theuniform standard established, then the inhaler should becomeinoperative, and a cut off mechanism is thus desirable. The chambercould have a resealable, refilling opening 31 to which a user can couplethe canister to a larger high-pressurized Heliox tank.

High pressure chamber 32 includes a housing 36 defining a third chamber38. Housing 36 includes an opening 40 on a top portion thereof and a gaspassage 42 on a side. Third chamber 38 communicates with both highpressure chamber 32 and equalization chamber 34. Equalization chamber 34is needed to produce a consistent volume of gas throughout the lifecycleof the high-pressure canister 32 independent of its inside pressure.This is achieved with the help of a simple regulator via the diaphragmplate 56. Gas will flow from the high chamber 32 to the equalizationchamber 34 until equalization chamber 34 has reached its nominalpressure, constant value much smaller than the high-pressure at whichthe gas is stored in the canister 32.

Equalization chamber 34 includes a housing 58 having a gasket 46disposed therein. Gasket 46 includes a gas passage 48 on a side thereoffor allowing gas disposed in third chamber 38 to communicate with secondchamber 34.

A piston 44 is slidably mounted within gasket 46 and within housing 36.Piston 44 includes a communication opening 50. Piston 44 is pusheddownwards with a spring 60 located inside chamber 38 to allow gascommunication between chambers 32 and 34. When the canister 32 isseparated from the inhaler, the spring 60 is pushing the piston 44sealing the canister by closing the opening 42. When the canister isinserted in the inhaler, the tip of the piston 44 will rest on thediaphragm 56, and pushing the piston 44 up inside chamber 38 just sothat high-pressure gas passage 42 is communicating with thecommunication opening 50. Communication opening 50 is designed toselectively allow gas 52 stored in high pressure chamber 32 tocommunicate with gas 54 stored in equalization chamber 34. A pressureplate 56 is also disposed within housing 58. One side of pressure plate56 is coupled to piston 44.

Through the use of high pressure chamber 32 and equalization chamber 34,inhaler 30 produces a desired gas pressure without requiring an externalpump or inhalation pressure from a patient. When the pressure inside theequalization chamber 34 is too low to allow inhaler 30 to be used, it isdesirable that the high-pressure Heliox 52 from high pressure chamber 32will fill into equalization chamber 34. Spring 60 and pressure plate 56are designed so as to facilitate this operation. As stated above, piston44 has a communication opening 50 that selectively allows high pressurechamber 32 to communicate with equalization chamber 34 through gaspassages 42 and 48 when passages 42, 48 are aligned with communicationopening 50.

Gas 52 applies pressure against a small area defined by the top ofpiston 44. The net force from gas 52 pressing on piston 44 is thepressure of the gas multiplied by the surface area of the top of piston44. This net force applied by the high-pressure side of high pressurechamber 32 on piston 44 works with the biasing force of spring 60 andagainst the force applied by gas 54 on pressure plate 56.

The spring constant of spring 60 and the surface area of pressure plate56 are chosen so that when equalization chamber 34 has receivedsufficient pressure to utilize inhaler 30, the force applied by gas 54on pressure plate 56 will exceed that of the force produced by gas 52 onpiston 44 on the high-pressure side of the device and the force of thespring 60. At such a time, the force applied by gas 54 will cause piston44 to move upward within housings 58 and 36. As piston 44 movesupwardly, communication opening 50 will move away from gas passage 48effectively stopping any additional high-pressure Heliox 52 fromentering equalization chamber 34. The spring 60 will push the piston 44downwards to allow gas passage from chamber 32 to chamber 34 no matterwhat the pressure is inside chamber 32. Since the surface of thepressure plate 56 is quite important, the two main forces balancing thepiston are the spring force and the pressure force from the equalizationchamber 34. The spring constant of spring 60 and the area of pressureplate 56 are thus selected for a specific pressure rating so that apatient will always receive the same volume of gas and dosage for theirapplications, independent of the pressure change in high-pressurechamber 32.

Once gas 54 is dispensed (i.e., inhaler 30 has been actuated and themedication in inhaler 30 is delivered to the patient), the pressureexerted by gas 54 on pressure plate 56 is lower and the high-pressureHeliox 52 along with the spring 60 will force piston 44 downwardlythereby repeating the cycle described above until equalization chamber34 once again has a desired pressure of gas therein.

An alternative to this delivery system can be done using a mechanicalactuation by the user. As the high-pressure chamber 32 is depressed, thepiston 44 will allow the gas to escape from the high-pressure gaspassage 42 and be stored into a secondary chamber. The amount of gasreleased into equilibrium chamber 34 is then defined by the volume ofthis secondary chamber. The gas is released from this chamber into theequilibration chamber 34 when the high-pressure cylinder 32 is returnedto its original position. In this configuration the housing 58 could beused as the secondary chamber.

The high-pressure Heliox 52 can be stored at, for example, 1,600 psig.Equalization chamber 34 effectively decompresses this gas so that it hasa pressure of, for example, 32 to 200 psig. Using 22 ml of the 200 psigHeliox, the gas will expand to 300 ml at a pressure of one atmosphere.This is a sufficient amount of gas for drug delivery in one inhalation.

It should be noted that the equalization chamber 34 can be part of theseparable high-pressure canister 32. In other words, the design of thedelivery of a constant volume of gas can be an internal mechanisminherent to a high-pressure canister that the user can buy independentlyof the rest of the inhaler, or it can be part of the inhaler itself.

Equalization chamber 34 contains a fixed volume of pressurized gas 54.This gas will be released in two widely different volumes to the rest ofthe inhaler. The first volume released is around 270 ml of gas; thesecond is roughly 1/10^(th) that value, or 30 ml. It is proposed herethat the creation of the two volumes occurs in separate activation,either triggered manually by the user (i.e. pressing a trigger twice orat two positions) or sequentially inside the device. The drawings willcover 2 different embodiments of the invention: mainly either deliveringtwo volumes of gas using a two-chamber piston (FIG. 2), or with the useof two gas orifices, one being a calibrated orifice (FIG. 3).

Option 1:

The two-volume delivery can be done first by having two-chambers as seenin FIG. 2. The novelty aspect lies in the presence of two internalchambers and a unique piston shape, selectively isolating the chambers.Option 1 also allows for the delivery of the two-volumes of gas to be aninside component of the high-pressure canister 32. The two-volumedelivery can be inherent to the canister design where the two chambersare an internal mechanism of the canister, along with the equalizationchamber. It is for that reason that the valve assembly has been designedto closely resembles existing MDI canister design. If the two-volumedelivery is thought of belonging to the inhaler instead, the pistonshape can be changed to ease its manufacturing.

The shape of the piston is adapted to deliver first with a low pushactivation a high volume of gas (i.e. 270 ml) that can be used to purgethe spacer. Using a higher push activation will deliver a much smallervolume of gas (i.e. 30 ml) to nebulize the drug. Releasing the stemvalve allows the two chambers to communicate with the equalizationchamber refilling them for the next use.

Equalization chamber 201 includes an internal housing 203 defining twodifferent size chambers 204 and 205. Housing 203 includes an opening 208on top for communication with the equalization chamber. First chamber204 communicates with second chamber 205 via opening 209, and theoutside via the opening 210 in the main piston 202. Second chamber 205communicates with both equalization chamber 201 and the first chamber204 via the openings 208 and 209 in housing 203.

A piston 202 is slidably mounted within the gasket 203. Piston 202includes a communication opening 210 comprising of a hollow passageterminated at the bottom of the piston. The communication opening 210 isdesigned to selectively allow gas stored in chamber 204 to communicatewith the outside of the canister. The unique shape of the piston 202allows for the two-process operation.

At rest, piston 202 is pushed downwards by spring 206 located inside thehousing 203, isolating the chambers with an isolation ring.Communication openings 208 and 209 are opened allowing filling of thesecond and third chamber 204 and 205 from the equalization chamber 201.When the user wants the delivery of the first volume of gas, piston 202is sliding upward relative to the chamber 201. The opening 210 is nowcommunicating with chamber 204, releasing the first initial large volumeof gas. In this position, piston 202 pushes against the isolation ringsurrounding opening 209, closing opening 209 and isolating chamber 204from chamber 205. All the gas in chamber 204 will leave untilequilibrium is reached with the outside of the canister.

To release the second volume of gas, the piston 202 is moved further up.Gas can now flow from chamber 204 to chamber 205 via opening 209, and tothe outside via opening 210. The O-ring 207 affixed to the piston 202will now isolate chamber 205 from the main high-pressure gas in thecanister 201 by sealing opening 208. Since opening 208 is smaller indiameter than the piston, it will also limit the maximum upward movementof the piston 202 and the overall amount of gas delivered in one dose.Since chamber 205 is much smaller than chamber 204, it will deliver asmaller volume of gas to be used for the drug delivery.

Option 2:

The other option is to control the delivery of the two volumes usingcalibrated orifices. In this case, the design of the high-pressurecanister is similar to existing ones, the novelty lying in the design ofthe inhaler main chamber.

The main process is located inside the inhaler, communicating with theequalization chamber 34 via a piston 302, as seen in FIG. 3. In thiscase, the canister 32 along with the equalization 34 can be a detachableitem of the inhaler; it will now be referred in general term as thecanister 301. The delivery of the two volumes is inherent of the inhalerbody.

Piston 302 is pushed open by a user-activated valve 311. The valve 311is encased inside a casket 312 which has two gas passages 315A and 315Bconnecting the high-pressure gas from the canister 301 to the rest ofthe inhaler. 315B is a calibrated orifice that will allow a very smallknown flow rate to the inhaler. For instance a 0.004″ diameter orificewill allow a volume in one-half second of 21 ml for pure helium at 200psig while 315A is a larger orifice, sealed by the secondary piston 313.Piston 313 is pushed against the casket 312 by the large diameter of thevalve 311.

When the valve 311 is first pushed up, it pushes up piston 302,releasing high-pressure gas from the canister 301 to the outside viaopenings 309 and 310. The hollow diameter of piston 311 is now at thesame level as the secondary piston 313. Aided by the spring 314, thepiston 313 slides towards the valve 311 opening channel 315A.High-pressure gas flows via both orifices 315A and 315B producing thelarge amount of gas needed for the purge bolus. When the second volumeof gas is desired, the valve 311 is pushed farther up. Due to theexpansion in the valve diameter, the piston 313 is pushed back against312 sealing orifice 315A. High-pressure gas can only flow via thecalibrated orifice 315B alone creating the small amount of gas needed tomix with and nebulize the drug. Valve 311 is then pushed back down,releasing piston 302, and sealing the canister 301.

Equalization chamber 34, after the process described above, now has adesired pressure of gas 54 within it. Upon actuation of inhaler 30, gas54 will be utilized by being injected into a gas passage 62 of a medicalstorage or drum section 64. Referring now also to FIGS. 1 and 4-6, drumsection 64 includes a housing 65 that contains a rotating drum 66 andincludes gas passage 62. An elastic material 67 is disposed between drumsection 66 and housing 65 so that drum 66 can rotate freely withinhousing 65 but still retain drugs stored therein. Drum 66 is made ofplastic or coated plastic to decrease or eliminate static electricity,which can lead to agglomeration of particles of an injected drug. Drum66 includes a plurality of tubes 68, 70 that are substantiallycylindrical and extend longitudinally therethrough. Drum 66 furtherincludes a substantially cylindrical bore 72 also extendinglongitudinally therethrough. Tubes 68 contain a powdered drugformulation to be administered to a patient, whereas tubes 70 are emptyand hollow to allow communication of gas 54 from equalization chamber 34to a spacer 96 so that spacer 96 can be rapidly filled with severalhundred ml of Heliox prior to injection of the fluidized dry powder drugformulation into spacer 96.

FIG. 1 shows an embodiment where drum 66 includes tubes 68 and so anattached spacer is not pre-purged. This is especially useful when thespacer is small in size. FIG. 4 shows an embodiment of drum 66 thatincludes tubes 70.

FIG. 4A shows a cross sectional view along line A-A of FIG. 4. As shownin FIG. 4A, tubes 70 are empty and have a diameter that is larger thanthe diameter of tubes 68. Tubes 68 contain a powdered medication 76. Thediameter of each tube 68 is dependent on the volume and weight of drypowder of a specific drug to be delivered. Both tubes 68 and 70 arepacked within rotating drum 66 so as to maximize the amount of dosesavailable per rotating drum. For each drug filled tube 68, there is acorresponding hollow tube 70. A preferred arrangement is for the drugfilled tubes and hollow empty tubes to be arranged in pairs vertical toeach other. A multitude of such tube pairs can exist.

Micronized dry powder drugs can be made in particle ranges frompreferably slightly smaller than 1 micron to 5 microns. A fluidizedparticle range of less than 1 micron to 3 microns is most beneficial foroptimal drug delivery to the deep lung for systemic diseases. However,particle sizes should be optimized for both the delivery system, i.e.the inhaler design, and the targeted location in the lung. Therapeuticdrugs to treat the upper or middle lung for respiratory diseases, can beup to 5 microns in size in their final fluidized and delivered form.

Referring to FIG. 4, when rotating drum 66 is to be used, drum 66 isplaced upon spindle 78 so that spindle 78 is inserted into bore 72 anddrum 66 is coaxial with spindle 78. As indicated by arrows 82, rotatingdrum 66 is selectively placeable upon and removable from spindle 78. Aplurality of ducts 80 are disposed between gas passage 62 and both tubes68 and 70 so as to provide a gaseous communication between theseelements.

Two ducts 80 may be used to feed Heliox from equalization chamber 34 tospacer 96 with gas flow occurring through ducts 80 first to tubes 70 andthen to corresponding tubes 68. After the allocated number of tubes perone concentric ring has been emptied, the ducts are moved to a differentconcentric ring and corresponding tubes. This can be accomplishedthrough a simple appendage on drum 66 engaging a switch, or, a contactswitch operated by low level current. Alternatively, one duct 80 mayprovide gas to both tubes 68, 70 which is on an assembly that moves, andwhich changes position moving from one concentric ring of tubes to theother.

For example, this can be done by a set of gears (not shown). Themultidose barrel will rotate after (or before) each use using a geardrive activated by an external trigger. Duct 80 will be moved graduallyto an inner concentric tube (if the tubes are arranged in spiral form orto the next concentric filled tube if all the tubes are concentric).Duct 80 can be also dropped suddenly after completing most of onerotation. This is accomplished by removing the last tooth of a gear sothat duct 80 can be forced into an inner track with the help of a spring(not shown.

In another embodiment of drum 66, illustrated in FIG. 5, all of thetubes 68 in drum 66 contain dry powder drug and there are nocorresponding hollow tubes 70. Instead, Heliox used to prefill spacer 96is channeled through a spindle 78 on which drum 66 is mounted androtates. This allows for a doubling of the number of tubes in drum 66that contain the dry powder drug formulation. In both embodiments, shownin FIGS. 4 and 5, tubes 68 shown in dark indicate tubes that still havemedication 86 a and 86 b within them. Tubes 68 that are open indicatetubes that no longer have medication to be dispensed within them.

In this embodiment, only one duct 80 at a time need be coupled to acorresponding tube 68. This is because spindle 78 is used to providecommunication of gas 54 with spacer 96. Additional ducts 80 could beused for a different concentric ring of tubes 68. The embodiment of FIG.5 would increase the number of tubes containing drug powder or liquid inrotating drum 66, raising the multi-unit dose capacity of a singledisposable plastic barrel.

If the embodiment of FIG. 5 were used, ducts 80 would act as a source ofpropellant and fluidizing energy for the drug in the tubes. Each duct isactivated by a mechanical means when the ducts are to be utilized.Alternatively, a single Heliox source needle can change position toaccess each circular row of drug bearing tubes in succession.

As shown in FIGS. 1, 4 and 5, a clear sealed plastic overlay 86 isdisposed on the front 86 a and back 86 b of drum 66 covering all tubes68. Plastic overlay 86 contains and protects the dry powdered drug 76from moisture, provides an anti-microbial barrier, and keeps tubes 68clean and moisture free for pre-dose generation of Heliox gas injectioninto the spacer 96.

Plastic overlay 86 will have a surface strength marginally less then thepressure of gas 54. When gas 54 is injected into drug filled tube 68,plastic overlay 86 a bursts inward into tube 68. A buildup of pressurefrom Heliox 54 then occurs in tube 68, and explosively blows plasticoverlay 86 b existing on the spacer side of tube 68 thereby fluidizingpowder 76 into the environment of the spacer.

The engagement of rotating drum 66 with ducts 80 is illustrated withreference to FIG. 6. Rotating drum 66 includes a receptacle 88 forhermetically receiving duct 80 therein. Rotating drum 66 can be designedso that plastic overlay 86 a covers the entire front of rotating drum 66and receptacle 88 is affixed over plastic overlay 86 a. Alternatively,receptacle 88 may have a plastic membrane similar to plastic overlay 86built into it. Duct 80 includes beveled portions 90 made of a strong butpliable material so that when ducts 80 are inserted into receptacle 88,a small amount of physical pressure is required to maintain a tightfriction based seal between receptacle 88 and duct 80 during injectionof the Heliox gas. Receptacle 88 further has a trapezoidal shapedappendage 92 designed to accept duct 80 on a hermetic fitting basis atthe pressure required for operation and drug powder fluidization.

Alternative embodiments of rotating drum 66 are shown in FIGS. 7 and 8where tubes 68 may contain, instead of powdered drug 76, a liquid drug69 disposed therein. In the embodiment shown in FIG. 7, a microporeaerosol nozzle 71 is disposed in tube 68 at an end opposite duct 80. Aswith the prior embodiments, plastic overlay 86 keeps liquid drug 69within tube 68 until it is desired that liquid drug 69 be administered.In this embodiment, a space 85 is provided between aerosol nozzle 71 andplastic overlay 86B. Space 85 could be 0.25 inches or larger. Aerosolnozzle 71 is a hard structure with micropores. Plastic overlay 86B willexpand and stretch before it ruptures so it should not lay on top of theaerosol nozzle 71. Space 85 will also prevent plastic overlay 86 fromsticking over aerosol holes in aerosol nozzle 71 when plastic overlay 86ruptures.

Referring to FIGS. 9 and 10, another embodiment of tube 68 is shown. Inthis embodiment, again tube 68 is divided into a liquid container part68 a and gas conveyer part 68 b. Liquid drug 69 is contained withinliquid container part 68 a through the use of plastic overlays 86 a,b.Tube 68 further includes a friction seat 124 that is designed toselectively mate with a fixed nozzle 126 of spacer 96. In FIG. 10,spindle 78 is shown as the conduit for compressed gas 54. It should beclear though that tubes 70 could also be used in a drum 66 that has afriction seat 124 which mates with a friction nozzle 126.

In the embodiments shown, where a fixed nozzle is implemented, when drum66 rotates to align a new drug to be administered, drum 66 is movedforward toward spacer 96 and press fitted therein. This forwardperformed movement may be accomplished mechanically or manually by thepatient.

In all of the embodiments discussed above, when gas 54 is applied totube 68, the application causes an explosion of plastic overlay 86 ablowing into chamber 68. This explosion, combined with the combinationof gas pressure plus drug 69, 76 inside tube 68 bursts the plasticoverlay 86 b covering the other side of tube 68. This bursting ofplastic overlay 86 provides a large explosive and subsequent turbulenteffect to fluidize powder 76 or aerosolize liquid drug 69. Thedrug-Heliox combination is then introduced to a spacer 96 (FIG. 1),which has an environment of about 270 ml of Heliox gas. An advantage ofthis method, is that the ducts do not have to penetrate a pre-scoredvapor barrier which might clog the duct but instead the ducts provide agas to blow out the plastic overlays based on a predetermined plasticfilm strength and gas pressure.

Disposable multidose drum 66 is designed so that it can only be insertedonto spindle 78 on which it rotates in the correct manner. That is, aposition where the front of the drum 66 is inserted correctly juxtaposedto where the Heliox source(s) ducts are located.

Referring now to FIG. 1, the operation of inhaler 30 will now beexplained. An activating trigger 94 is disposed on drum section 64.Trigger 94 can have several stops like a multi-action pistol trigger, ormay have an activating button plunger with the same multi-actioninducing activities. When trigger 94 is depressed, drum 66 is rotatedabout spindle 78 to a correct position for the next dose. An inhalationport door 98 coupled to a mouth piece 99 of spacer 96 closes, therebyinhibiting a user from inhaling gas disposed within spacer 96.Alternatively, inhalation port door 98 could be first left open so thatthe air in spacer 96 is more efficiently purged out (as discussedimmediately below). Thereafter, inhalation port door 98 is closed asabove. Yet another embodiment includes using a combinationpressure/vacuum port (not shown) which opens to let air out during thepurging phase and closes during the drug delivery phase.

If an embodiment shown in the drawings is used, a quantity of 230-270 mlof Heliox gas is injected into spacer 96 from equalization chamber 34 togas passage 62, through tubes 70 or spindle 78, through another gaspassage 63 (not shown in figures) in housing 65 and finally through acompressed gas input port of spacer 96. The air in spacer 96 is pushedout or purged through a pressure port 100 so as to assure as close to a100% Heliox is present in the ambient spacer environment as possible.The Heliox gas provides both a spacer environment for settling of theheavier undesirable particles, and provides a large bolus front wave ofgas in which the desired fine particle fraction will be entrained duringinhalation. This will provide a sufficient amount of volume of Helioxgas to have the desired effect on delivery of particles in to the deeplung.

In the embodiment shown in FIG. 1, the spacer 96 is not necessarypre-purged. Therefore, all the volume of Heliox in the equalizationchamber is used to fluidize and deliver the drug only. If pre-purge isdesired, the first volume of Heliox delivered by any option presented inFIGS. 2 and 3 is first sent through the tubes 70 or 78 to purge theinside of spacer 96 then drum 66 rotates, allowing the second volume ofHeliox to nebulize the drug. A double action trigger can be used toactivate the process in sequence as presented in FIGS. 2 and 3.

When the process of filling spacer 96 with gas 54 ends, inhaler 30,based on a sequence automated or manually activated by trigger 94,shoots 30 to 70 ml of gas 54 obtained via the options presented in FIGS.2 and 3 into tube 68 containing the drug formulation. The gas fluidizespowder drug 76 (or aerosolizes drug 69), driving the drug through druginput port 68 into spacer 96, and causes turbulence which helps tofurther fluidize and deagglomerate the drug. In fact, one port could beused to deliver both the compressed gas alone, and a combination of thecompressed gas and drug.

Alternatively, Heliox gas 54 used to aerosolize drug 76 or 69 may beprovided in two pulses, of, for example, 60% and then 40% of the totalintended volume. This procedure assures all powder 76 from tube 68 isinjected into spacer 96, and further adds turbulence to spacer 96 sothat the particles are kept separated.

At a pre-determined period of time thereafter, e.g. 0.5 to 5 seconds, amechanical timer opens inhalation port 98 so that the patient can inhalecloud of particles. A combination of a spring, gear and wire (not shown)attached to trigger 94 can be used to make inhalation port door 98 closewhen trigger 94 is depressed. Depressing trigger 94 also activates theHeliox purge at the same time. When the patient releases trigger 94, thespring, gear and wire open inhalation port door 98 and start the drugdelivery. A vacuum/pressure valve 104 will close automatically untilinhalation door 98 opens and will equalize the pressure inside spacer 96until the patient has finished inhaling.

As the patient inhales cloud of particles, a vacuum begins to form inspacer 96. At a certain pressure, vacuum/pressure valve 104 opensallowing ambient air into spacer 96. By opening vacuum/pressure valve104, the patient may continue a steady deep inhalation of room airfollowing the Heliox bolus, slug or gas front entraining particle cloud.Vacuum/pressure valve 104 also ensures that larger particles that maysettle on the bottom of spacer 96 do not get inhaled by a user.Vacuum/pressure valve 104 can be opened/closed automatically. Forexample, it can be made of a piece of flexible metal strip. Atatmospheric pressure, the strip will line up perfectly with the wall ofspacer 96. When the Heliox builds up excess pressure during purging,vacuum pressure valve 104 will coil upward, keeping the Heliox in. Wheninhalation port door 98 is opened by the trigger wire, the pressure willdrop to normal. During the drug delivery, the patient will breathe inmuch larger volume of gases (500 ml to 1.5 liters) than the 230-270 ml.During the inhalation, a vacuum will form as the Heliox with the drugwill be inhaled. Now the metal strip will coil inwards to allow air torush in.

This structure prevents excess pressure or velocity of the Heliox/drugcombination. Moreover, since the whole process occurs within a fewseconds, it is not necessary to make the system leak proof or strongenough to sustain any particular high pressure.

Spacer 96 provides the following benefits:

a) slows down the velocity of the Heliox gas plus drug formulationinjected into the spacer;

b) allows sufficient turbulence to keep the small desirable particlessuspended and separated;

c) allows the heavier particles unsuitable for pulmonary drug deliveryto settle out or be trapped in the spacer; and

d) provides a bolus, slug or initial front of gas plus drug formulationthat is 100% Heliox, followed, thereafter, by air as part of the samecontinuous breath.

Spacer 96 may be further provided with a scented receptacle 110 disposedon an upper and outer part of the spacer near to where a patient's nosewould be.

Receptacle 110 may be a scented strip containing essence of vanilla,mint, or another scent, and is placed near the nose to make the use ofthe inhaler pleasant for children and older adults who dominate theusage population.

Spacer 96 should be constructed of a plastic, or provided with an innercoating, that eliminates the generation of static electricity. This isbecause static electricity imparted to the drug particles injected intothe spacer could result in clumping and adversely affect the dosedelivered to the patient.

It is desirable for spacer 96 to incorporate in its inhalation port door98 an apparatus to prevent the accidental exhalation by the patient intospacer 96 prior to inhalation, so as to avoid mixing of exhaled gaseswith the Heliox and suspended drug cloud of particles, and to avoidagglomeration of the particles due to exhaled moisture. It is alsodesirable for inhalation port door 98 to be closed upon introduction ofthe Heliox ambient atmosphere and Heliox plus drug formulation intospacer 96, so that only Heliox is in spacer 96 and a minimal amount ofthat Heliox is lost external to spacer 96.

Spacer 96 can be made of rough materials on its surface. The roughsurface serves two different purposes. It can slow down theHeliox-powder mixture to a laminar flow by inducing additional boundarylayer drag force. The rough surface can also provide a trap to hold thelarge particles.

After the injection of the Heliox gas and Heliox plus drug formulationinto the spacer, it is further desirable to reduce the Heliox velocityimmediately prior to transit from turbulent flow to laminar flow. Animpact plate (ball or other object) and a diffuser can accomplish thisreduction in velocity. Referring again to FIG. 1, a diffuser 112 isdisposed between spacer 96 and drum section 64.

Diffuser 112 includes an impact ball 114 at a portion of diffuser 112that is proximate to gas passage. Impact ball 114 is used to reduce theinitial high velocity of highly turbulent gas and drug that entersdiffuser 112. When gas and drug is injected into diffuser 112, ahigh-energy flow may concentrate in the center of the unit. Impact ball114 helps avoid this channeling effect. Diffuser 112 is shaped as anexpansion cone to slow down the gas-powder mixture. The size of diffuser112 is dependent on the desired gas-powder mixture velocity hitting theback of the throat. The velocity should be low enough so that the flowis laminar. At an inhalation flow rate of 60 L/min (often the necessaryflow rate required by some DPIs to release the drug), the Reynoldsnumber is 670 for pure helium compared to 5,400 for air. Using a certainmix of helium and air changes the Reynolds number accordingly, as shownin Table 3. Even if the Reynolds number is low enough so that it fallsinto a laminar category, the flow might still be turbulent due to theroughness of the surface for instance. Spacer 96 can be combined withdiffuser 112 so that the large particles can drop out of particle cloudin spacer 96.

TABLE 3 Effect of concentration of helium on flow regime. Percentage ofHelium (balance oxygen) % Helium 0 20 40 60 80 100 Diameter of 1.8throat (cm) Inhalation 60 rate (L/min) Velocity (m/s) 3.9 Gas density1.43 1.18 0.93 0.68 0.43 0.18 (g/cc) Viscosity 204 201 198 196 193 190(μP) Reynolds 4950 4140 3310 2460 1670 666 number Flow Regime* T T TTrans Trans L *T = Turbulent, Trans = Transitional, L = Laminar

The function of impact ball 114 can be incorporated into spacer 96.Spacer 96 could include an impact plate disposed at an end of spacer 96proximate to inhalation port door 98. In this design, the injectedHeliox stream and drug particles would hit impact plate causingimpaction and turbulence, and resulting in a reduction in the velocityof particle cloud. The impact plate could be tilted so that the injectedHeliox and drug particles would reflect off impact plate, therebyresulting in the accelerated settling of heavier particles and theformation of a cloud of desired particles containing a desired fineparticle fraction.

Diffuser 112 and spacer 96 can also include a flow-straightening device.For example, diffuser 112 and spacer 96 can be sub-divided into parallelchannels. The channels will adsorb all the energy from the random motionof a turbulent flow.

Referring to FIG. 11, there is shown a flow straightening device thatcan be used in spacer 96. Spacer 96 further includes a plurality ofshelves 122 disposed proximate to inhalation port door 98. Shelves 122function so that gas 54 passes over or just above and below shelves 122,thereby helping to induce a straightened flow of the Heliox andentrained particles into the patient.

It should be made clear that spacer 96 and diffuser 112 are merelyadditional options that could be used with inhaler 30. A patient may usespacer 96 only, diffuser 112 only, or neither appendage when usinginhaler 30. If spacer 96 is not used, mouthpiece 99 should be placed onthe end of diffuser 112. If diffuser 112 is also not used, thenmouthpiece 99 should be placed on an end of gas passage 62. It shouldalso be clear that when mouthpiece 99 is not disposed on spacer 96, itis not necessary to further include inhalation port door 98.

Referring to FIG. 12, there is shown another embodiment of theinvention. Similar elements contain the same reference numeralsdescribed above and their description is omitted for the sake ofbrevity. The inhaler comprises, a venturi section 142 coupled to chamber34. Venturi section 142 includes a liquid drug reservoir 144 having astore of liquid drug 146 contained therein. A gas passage 148selectively provides communication between equalization chamber 34 and aventuri 150. The inlet of venturi 150 communicates with gas passage 148.The outlet of venturi 150 communicates with diffuser 112. The throat ofventuri 150 communicates with a liquid metering tube 152 coupled toliquid drug reservoir 144.

As would be understood by one with ordinary skill in the art, when gas52 passes through venturi 150, since the throat of venturi 150 isconstricted, a decrease in pressure of gas 54 is experienced at thethroat of venturi 150. This apparent vacuum sucks a quantity of liquiddrug 146 out of liquid drug reservoir 144. This quantity of liquid drug146 is aerosolized by gas 54 and injected into diffuser 112. Clearly,diffuser 112 is not necessary as the gas/drug combination could godirectly to spacer 96 or to the patient.

Another embodiment of the invention would use ultrasonic nebulization.Ultrasonic nebulization is more efficient in delivering properly sizedparticles and reducing dead (unused) volume of medication. Its maindisadvantage comes from an increase in temperature over long use. Thisis avoided in the present invention since the nebulization will onlyoccur via short puffs. Although not as extensively used as the Venturiprinciple, it is in the core of new inhaled drug delivery systems suchas the AeroDose (AeroGen Inc, Sunnyvale, Calif., patent U.S. D4,745,36),Premaire Metered Solution Inhaler (Sheffield Pharmaceuticals), or theVibrating Membrane Nebulizer (Pari GmbH, Germany). Ultrasonicnebulization uses the excitation of a piezoelectric crystal vibrated athigh frequency to create waves in the liquefied drug solution placeddirectly above the crystal. The oscillation waves then disrupt thesurface and create a geyser-like behavior at the surface, nebulizing thedrug that is then carried by the Heliox gas passing above the surface onits way to the spacer. The practical means is not specifically addressedhere, only the concept of adding ultrasonic nebulization to thehelium/Heliox inhaler is presented. Ultrasonic nebulization can easilybe adapted to the present invention.

In all of the above arrangements, the spacer is designed to accommodatethe total volume of Heliox gas to be injected into it both as a bolus ofgas and with the drug dose. The spacer is designed so that the Helioxgas displaces the ambient air that is in the spacer prior to theintroduction of Heliox and then replaces it with Heliox gas and drugformulation.

Sufficient gas pressure is needed to optimally fluidize the powder (oraerosolize the liquid drug) in a manner that particles of the desiredsize range and grouping are generated. Therefore, it is desirable tohave a cut off pressure valve which, when the pressure in equalizationchamber 34 is insufficient to provide sufficient Heliox volume to fillspacer 96 and a pressure wave to optimally fluidize or aerosolize thedrug, the inhaler will cease to function. Such a cut off switch could becomprised of a pin hook that is effective to disengage trigger 94. Pinhook could be coupled to a spring that could be in turn coupled to adiaphragm. Thus, when the pressure in equalization chamber 34 is highenough, the diaphragm would be pushed towards equalization chamber 34thereby elongating the spring. This elongation of the spring clears thehook from trigger 94 and allows trigger 94 to operate. When there isinsufficient pressure in equalization chamber 34, the hook engagestrigger 94 and thereby precludes trigger 94 from operating. Anotherembodiment includes employing a pre-calibrated Heliox gas cylinder thatwill provide more than enough Heliox for all the medication inside drum66. Furthermore, a pressure activated flag or signal, could beimplemented to tell the user that a cartridge needs to be replaced.

Since it is critical that patients have access to medication whenneeded, a counting method is desired concerning the number of dosesremaining. A counting method can be placed above or by each drug tube indrum 66 with an indicator for indicating the number of doses left. Eachapplication of trigger 94 will rotate drum 66 once and when themedication is empty, the indicator on drum 66 would indicate that thereis no medication left in the device.

As the inhaler in accordance with the invention can deliver differentdrugs by use of different multidose drug drum, a clear label with blackletters stating the drug and potency and a color band coding system canbe affixed to the outside of each drum. This clear label material willnot obstruct the contents of the tubes within the barrel containing thedrug formulation. These features also provide an added safety measure byallowing a visual verification of remaining doses, in addition to oneprovided by a simple automatic counting mechanism which is a part of thedevice which tells the user how many doses have been used, or how manydoses are left. The “zeroing” of said device can be done manually, or,be automatically done by a feature of the barrel such as an appendage.

One advantage of this system, is that drug containing tubes in a singledisposable multi unit dose barrel can contain the same drug, or, asequence of drugs to be taken over the course of a day. For exampletubes 1, 2, 3, 4 may contain a sequential medication group and tubes 5,6, 7, 8 a repeat of the same medication group with each dose, forexample, within tubes 1-4 to be inhaled every 6 hours.

Examples of classes of drugs being investigated and formulated forpulmonary administration, which may be administered with the invention,include, but are not limited to, those for chronic obstructive lungdiseases such as the classes of agents commonly referred to asanticholinergic agents, beta-adrenergic agents, corticosteroids,antiproteinases, and mucolytics, and include such specific drugs.

Other therapeutic pharmaceuticals for respiratory disease use in drypowder and/or liquid form with which the invention could also be usedinclude, but are not limited to, benzamil, phenamil, isoproterenol,metaproterenol, Beta 2 agonists in general, Proctaterol, Salbutamol,Fenoterol, ipratropium, fulutropium, oxitropium, beclomethasonedipropionate, fluticasone propionate, salmeterol xinafoate, albuterol,terbutaline sulphate, budesonide, beclomethasone di propionatemonohydrate, surfactants such as colfosceril palmitate, cetyl alcoholand tyloxapol, P2Y2 agonist (rapid stimulates mucus and is potentiallyfor use in CORD and OF), aerosolized dextran (for OF), and mannitolpowders (for bronchial provocative challenge). An example of anothertherapeutic drug that could be delivered by the invention is Pentamidinefor AIDS related therapy.

Examples of proteins and peptide hormone drugs that may be administeredwith the invention, which may or not be glycosolated, includesomatostatin, oxytocin, desmopressin, LHRH, nafarelin, leuprolide, ACTHanalog, secretin, glucagon, calcitonin, GHRH, growth hormone, insulin,parathyroid, estradiol and follicle stimulating hormone andprostaglandin El.

In addition, genes, oligonucleotides, anti-coagulants such as heparinand tPA, anti-infective to treat localized and systemic bacterial orfungal infections, enzymes, enzyme inhibitors, vaccines, anesthetics,pain killers, and agents that can turn certain types of receptors on,off, or enhance their response are possible therapeutic drugs or actioninducing substances which may be delivered via the invention.

Ergotamine for the treatment of migraine headaches and nicotine tosubstitute for and eventually eliminate cravings for tobacco, are alsotherapeutic formulations that may be administered by the invention,along with insulin.

Furthermore, controlled release drugs such as those that are liposomebased and which are designed for pulmonary drug delivery to treatrespiratory and systemic diseases over a period of time due to thechronic nature of the illness or the mode in which the illness respondsto medication, or the mode in which the medication operates, may beadministered by the invention.

Existing DPIs use the patient's inhalation alone, the patient'sinhalation assisted by a propeller, or compressed air generated by ahand pump in a DPI, to fluidize the dry powder drug formulation. One DPIalso uses compressed air in a plastic pillow that contains the drypowder drug formulation as an aid to fluidization.

The present invention offers several advantages over these approaches tofluidizing a dry powder drug formulation. First, the volume of gas(Heliox) and its pressure are independent of the operator's inhalationvelocity, ability to generate a given level of inhalation velocity (if,as in some devices, a minimum threshold is required for release of thepowder for fluidization), or physical motion. No batteries need to bechecked and replaced periodically as is required for the propellerdriven system. Compressed air does not have to be pumped prior to eachdosing.

DPIs that rely on inhalation power, a propeller, or hand pumpedcompressed air, all use air that is from the environment where the useris present. If the air is humid, it can cause clumping of the micronizeddry powder drug formulation, resulting in larger particles that may notreach the upper lung, let alone the deep lung. A factory producedcompressed Heliox source can be produced as a desiccated dry gas,eliminating this problem in humid climates. This in turn, would causevariability in the fluidization, deagglomeration, and post clumping ofdry powder drug formulations, which in turn effects the fine particlefraction available for pulmonary administration and effective therapy.

A factory-produced source of pressurized Heliox also provides theadvantage of a high velocity gas stream, which provides the advantage ofa more forceful impact on and fluidization of a dry powder drugformulation, compared to the force generated by inhaled air, batterypowered propeller assisted air, or hand pumped compressed air. Theresult is that the powder can be fluidized and deagglomerated morecompletely, with the result being a more consistent and effective use ofa unit dose of the formulation, and potentially a reduction in thenominal drug powder formulation that must be loaded into the inhaler asmore is consistently deliverable.

The use of tubes, instead of blisters and reservoirs of powder as in theprior art, allows the effect of the gas pressure to be magnified interms of velocity generated and impact of the gas on the particles.

The use of a multi-unit dose disposable drum with pre-loaded tubes ofdrug formulation prepared under factory controlled conditions, is animprovement over the prior art, which uses a barrel permanently open onone end, into which the user must insert capsules, and after use, removethe capsules. First, there is the factor of user variability in loadingthe capsules in the prior art, and of loading the right capsules if auser takes more than one medication that may be administrable by thesystem. Second, powder can remain in the capsule and tube due tophysical obstruction of airflow by the debris after the capsule ispunctured. Third, because the broken capsules have to be removed by theuser as the barrel is fixed and not merely used and disposed, there isalso residual powder in the tube. This residual powder can alter thedose delivered to the patient when another capsule is put into that tubeand used, or, worse, if another medication is administered, the twopowders might mix with an unknown variable, or perhaps undesired effecton the patient system.

Another advantage of the compressed low molecular weight Heliox gas isthat it can also be used for delivering liquid drug formulations. Helioxis a much better liquid aerosolizing/atomizing agent because of its highvelocity of release and it does not have the same coolingcharacteristics of liquid CFCs.

In the present invention, the multidose insert containing multiplesealed unit doses of liquid drug, or a reservoir multidose liquid drugsource, is stored separately from the compressed gas. In contrast, inMDIs, the propellant and drug formulation are stored together, alongwith many other additional additive ingredients. In the case of liquiddrug suspension formulations, the MDI must be shaken before each use totry to achieve a uniform consistent dosing. Additionally, temperaturechanges can make the drug compound, which is packaged with thepropellant, come out of solution.

The uniquely designed spacer reduces the high velocity of the Heliox gasand the dry powder particles or aerosolized droplets of liquid drug thathave been generated, resulting in the desired settling within the spacerof the larger particles which are neither desirable nor effective forpulmonary drug delivery. Existing spacers are filled with ambient airprior to the entrance from the MDI or DPI of air plus entrained drugpowder or liquid drug droplets.

In the present invention, the spacer is pre-filled with Heliox gas priorto the mixture of Heliox gas and entrained drug powder or liquiddroplets entering the spacer. This provides a unique gas environment fora) a differential settling of heavier particles than air, and b) a largevolume bolus of Heliox plus a desired fine particle fraction which isthen inhaled by the patient, followed on a continuous inhalation basiswith air, with the Heliox and particles being the inhaled tidal gasfront. The spacer also can have laminar flow shelves, which help inducethe laminar flow of Heliox plus entrained particles from the “cloud” offluidized powder or aerosolized liquid drug formulation upon inhalationby the patient. The spacer reduces the velocity of the gas stream to anacceptable cloud of particles, the undesirable particles settle out, andthe resulting cloud of remaining particles that are of the desiredparticle size range can be inhaled. The laminar flow shelves aid in theintroduction of a laminar flow out of the spacer of the helium gas andentrained particles.

Then, upon inhalation, it is highly desirable to keep the particles ofthe desired size range from settling. With viscous drag greater than thegravitational settling velocity, the fine solid particles can besuspended indefinitely without settling. On the other hand, additionalviscous drag will cause an excess pressure drop. It is therefore,desirable to control the viscosity.

The ability of this invention to generate initial high turbulent flowand provide rapid flow deceleration is important to the performance ofthe inhaler for powdered drug delivery.

A high pressure chamber and an equalization chamber are provided so thatHeliox gas can be stored efficiently under a high pressure and also beused as a propellant to fluidize or aerosolize a drug at a lowerpressure. Using a mechanical way to systemically provide two widelydifferent volumes of gas allows to create first a bolus of gas then asecond volume of gas to fluidize, nebulize the drug, independently of avariable user activation. By providing a disposable chamber for storingmedication, a user does not have to manually insert and remove drugs andthere is no concern that the tubes carrying these drugs will becomesoiled from prior administered medication. By injecting a hermeticallysealed spacer with some Heliox prior to injecting the same spacer with aHeliox/drug combination, the heavier particles in the Heliox/drugcombination can be settled quicker than in air. Also, a large volumebolus of Heliox plus a desired fine particle fraction can be inhaled bythe patient, followed by inhalation of air, with the Heliox andparticles being the inhaled tidal gas front. The drug/Heliox combinationin the spacer is also less susceptible to external factors such ashumidity in the ambient air as the spacer is hermetically sealed.Finally, by using Heliox as a propellant, a drug fluidized oraerosolized by this propellant has a better chance of navigating theairways and reaching desired portions of the lung.

The main costs of the inhaler are the drug and the manufacturing/parts.The cost of Heliox, while being an expensive gas by itself, is less thanthe other costs. There is then an incentive for the patient to be ableto use the inhaler for a much longer period than the limited number ofdoses available in the canister. Providing the user with an in-home meanto refill his canister allows him to continue using his inhaler forlonger periods of time without going to the pharmacy or doctor. Thehigher cost of the inhaler would then be paid for by the longer use.

While preferred embodiments of the invention have been disclosed,various modes of carrying out the principles disclosed herein arecontemplated as being within the scope of the following claims.Therefore, it is understood that the scope of the invention is not to belimited except as otherwise set forth in the claims.

1-50. (canceled)
 51. A method of introducing a drug from a metered doseinhaler into a spacer, the metered dose inhaler comprising an outlet inflow communication with the spacer, a drug storage section, a gasequalization chamber coupled to the drug storage section and the outlet,a propellant gas disposed in the gas equalization chamber at apredetermined pressure and a drug source disposed in the drug storagesection, the method comprising the steps of: injecting a first volume ofthe propellant gas from the gas equalization chamber directly into thespacer via the outlet; injecting a second volume of propellant gas fromthe gas equalization chamber into the drug storage section to aerosolizethe drug, thereby producing a drug cloud; and directing the drug cloudinto the spacer via the outlet.
 52. The method of claim 51 wherein thepropellant gas contains helium.
 53. The method of claim 51 wherein thefirst volume of the propellant gas is about 9 times the second volume ofpropellant gas.
 54. The method of claim 51 wherein the step of directingthe drug cloud into the spacer further comprises inducing a laminar flowof the drug cloud in the spacer.
 55. The method of claim 51 wherein thepressure of the propellant gas in the gas equalization chamber isbetween about 20 psig and 100 psig.
 56. The method of claim 51 whereinthe steps of injecting a first volume of the propellant gas andinjecting a second volume of propellant gas are performed successively.57. A method of introducing a drug from an inhaler into a spacer, theinhaler comprising a high pressure gas container, a gas equalizationchamber fluidically coupled to the high pressure gas container, a drugstorage section containing a drug source and selectively coupled to thegas equalization chamber and an outlet coupled to the gas equalizationchamber and the drug storage section, the method comprising the stepsof: supplying a propellant gas from high pressure gas container to thegas equalization chamber; delivering a first volume of the propellantgas from the gas equalization chamber directly into the spacer via theoutlet; delivering a second volume of propellant gas from the gasequalization chamber into the drug storage section to aerosolize thedrug, thereby producing a drug cloud; and directing the drug cloud intothe spacer via the outlet.
 58. The method of claim 57 wherein thepropellant gas contains helium.
 59. The method of claim 57 wherein thefirst volume of the propellant gas is greater than about 5 times thesecond volume of propellant gas.
 60. The method of claim 57 wherein thepressure of the gas in the high pressure gas container is between about100 psig to 1600 psig and the pressure of the propellant gas in the gasequalization chamber is between about 20 psig and 100 psig.
 61. Themethod of claim 60 wherein the gas from the high pressure gas containerrefills the equalization chamber with propellant gas after delivery ofthe first volume and second volume of the propellant gas.
 62. The methodof claim 57 wherein the steps of delivering a first volume of thepropellant gas and delivering a second volume of propellant gas areperformed successively.